The Regulatory Mechanisms Of Reversible Histone Acetylation On Human IL-5 Gene Transcription

The expression of interleukin-5 (IL-5) has been correlated with the maturation and differentiation of eosinophils, and is considered to be a cytokine responsible for allergic inflammation. In this study, we explored the possible regulatory mechanisms of reversible histone acetylation on human IL-5 gene transcription. We report here that inhibition of HDAC activity by Trichostatin A (TSA) and sodium butyrate (NaBu), two specific HDAC inhibitors, resulted in an increase of IL-5 transcription both in vivo and in vitro. We demonstrate that both the IL-5 mRNA expression and IL-5 protein production were stimulated by TSA and NaBu treatments. Chromatin immunoprecipitation (ChIP) assays showed that treatments of TSA and NaBu caused hyperacetylation of histones H3 and H4 at the IL-5 gene promoter in Jurkat cells, which consequently promoted the exogenous luciferase activity driven by this promoter. The reversible acetylation catalyzed by p300 and HDAC4 altered the status of histone acetylation at the promoter region of IL-5 gene, and in turn regulated the activity of IL-5 gene. The nucleo-cytoplasmic shuttling of HDAC4 was shown to play an important role in the suppressive function of HDAC4 in IL-5 gene expression. Point mutation and reporter ChIP studies determined that the four transcription factors binding on the IL-5 gene promoter, i.e., C/EBPβ, GATA-3, NFAT and YY1, were essential for the recruitment of HDAC4 and the stimulating roles of HDAC inhibitors on IL-5 gene. Consistent with these observations, HDAC4 was found to form protein complexes with GATA-3 and YY1, and to co-exist in nuclei with GATA-3. Based on the experimental data arising from this study, we propose that the unique regulatory mechanism of IL-5 gene transcription involves the reversible histone modification catalyzed by HDAC4 and p300, which are recruited by the transcription factors. The dynamic balance in IL-5 transcriptional regulation is achieved through interactions among HATs/HDACs, histones and the transcription factors. These data will contribute to elucidating the unique mechanisms of IL-5 transcriptional control, which is crucial to the development of new therapeutic strategies for IL-5-related allergic diseases.